Proteolysis-Targeting Chimeras Enhance T Cell Bispecific Antibody-Driven T Cell Activation and Effector Function through Increased MHC Class I Antigen Presentation in Cancer Cells.

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  • Additional Information
    • Source:
      Publisher: American Association of Immunologists Country of Publication: United States NLM ID: 2985117R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1550-6606 (Electronic) Linking ISSN: 00221767 NLM ISO Abbreviation: J Immunol Subsets: MEDLINE
    • Publication Information:
      Publication: Bethesda, MD : American Association of Immunologists
      Original Publication: Baltimore : Williams & Wilkins, c1950-
    • Subject Terms:
      Antibodies, Bispecific/*immunology ; Antigen Presentation/*immunology ; CD8-Positive T-Lymphocytes/*immunology ; Chimera/*immunology ; Histocompatibility Antigens Class I/*immunology ; Lymphocyte Activation/*immunology ; Neoplasms/*immunology; Antigens, Neoplasm/immunology ; Biomarkers, Tumor/immunology ; Cell Line, Tumor ; Epitopes, T-Lymphocyte/immunology ; Humans ; Proteolysis ; Receptors, Antigen, T-Cell/immunology
    • Abstract:
      The availability of Ags on the surface of tumor cells is crucial for the efficacy of cancer immunotherapeutic approaches using large molecules, such as T cell bispecific Abs (TCBs). Tumor Ags are processed through intracellular proteasomal protein degradation and are displayed as peptides on MHC class I (MHC I). Ag recognition through TCRs on the surface of CD8 + T cells can elicit a tumor-selective immune response. In this article, we show that proteolysis-targeting chimeras (PROTACs) that target bromo- and extraterminal domain proteins increase the abundance of the corresponding target-derived peptide Ags on MHC I in both liquid and solid tumor-derived human cell lines. This increase depends on the engagement of the E3 ligase to bromo- and extraterminal domain protein. Similarly, targeting of a doxycycline-inducible Wilms tumor 1 (WT1)-FKBP12 F36V fusion protein, by a mutant-selective FKBP12 F36V degrader, increases the presentation of WT1 Ags in human breast cancer cells. T cell-mediated response directed against cancer cells was tested on treatment with a TCR-like TCB, which was able to bridge human T cells to a WT1 peptide displayed on MHC I. FKBP12 F36V degrader treatment increased the expression of early and late activation markers (CD69, CD25) in T cells; the secretion of granzyme β, IFN-γ, and TNF-α; and cancer cell killing in a tumor-T cell coculture model. This study supports harnessing targeted protein degradation in tumor cells, for modulation of T cell effector function, by investigating for the first time, to our knowledge, the potential of combining a degrader and a TCB in a cancer immunotherapy setting.
      (Copyright © 2021 by The American Association of Immunologists, Inc.)
    • Accession Number:
      0 (Antibodies, Bispecific)
      0 (Antigens, Neoplasm)
      0 (Biomarkers, Tumor)
      0 (Epitopes, T-Lymphocyte)
      0 (Histocompatibility Antigens Class I)
      0 (Receptors, Antigen, T-Cell)
    • Publication Date:
      Date Created: 20210703 Date Completed: 20211025 Latest Revision: 20211025
    • Publication Date:
      20231215
    • Accession Number:
      10.4049/jimmunol.2000252
    • Accession Number:
      34215653